PARTNERS WITH
Cisplatin
Platinum based Alkylating agents
MECHANISM OF ACTION
Binds to DNA and inhibits DNA replication leading cell death/ Excreted in urine
MECHANISM OF KIDNEY INJURY
Cellular toxicity of S3 segment PCT. Vasoconstriciton. PCT apoptosis (ATI). PCT-incresed uptake by OCT, decreased expression of sodium dep glucose transports. Decreased expression of magnesium transports. Generation of reactive ox species. Fanconi and TMA
CLINICAL KIDNEY SYNDROME
AKI, Proteinuria/Albuminuria, Fanconi's Syndrome, CKD, mild proteinuria, salt wasting syndrome, polyuria
CARDIOVASCULAR ADVERSE EFFECTS
bradycardia, tachyarrhythmia, ACS, hypertension, and CHF
LYTE ABNORMALITIES
Hypomagnesemia, Metabolic acidosis (HAGMA, NAGMA), Non Nephrotic range proteinuria, mild proteinuria,
RISK FACTORS
Preexisting kidney dysfunction, female sex, old age, hypomagnesemia, hypoalbuminemia, smoking and other concomitant nephrotoxic agents use.
MITIGATION STRATEGIES
Volume expansion with NS pre and post infusion, Mg supplementation to avoid hypomagnesemia, correct electrolyte abnormalities.
SUGGESTIONS
Hold offending drug and rechallenge after AKI/proteinuria resolves, Volume expansion, Check TMA work up (send haptoglobin, peripheral smear, LDH), dose reduction if possible, RRT if develops severe AKI/ATN with usual indications
NOTES/COMMENTS
eGFR of 46-60 ml/min> 75% of Cisplatin dose
eGFR of 30-45 ml/min > 50% of dose
eGFR <30 ml/min, avoid
PHARMACOKINETICS
Molecular Weight
300.05 g/mol
Volume of Distribution
11 to 12 L/m2
Plasma Protein Binding
> 90%
Metabolism
Nonenzymatic; inactivated (in both cell and blood stream) by sulhydryl groups; covalently binds to glutathione and thiosulfate
Bioavailability
---
Half-life elimination
Decline in a biphasic manner with terminal half-life of 36 to 47 days; initial half-life of 25 to 49 minutes
Time to peak
90 to 150 minutes
Excretion
Feces (insignificant); > 90% renal (13 to 17% with 1 hour)
Dialyzable?
Free cisplatin is dialyzable and hence administered on non HD days or post HD (50% of the standard dose)
REF:
Uptodate
ACKD part 2 (conventional chemotherapy and nephrotoxicity)
ADDIKD
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter12.pdf
PATHOLOGY SLIDES:
ENTRY UPDATES:
Tanazul Pariswala, MD
United States
Sep 25, 2022